Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors, most recently culminating in the FDA-approval of vismodegib (Genentech/Roche) for the treatment of locally advanced or metastatic basal cell carcinoma. Vismodegib and other hedgehog pathway antagonists currently being evaluated in the clinical setting are small molecules that act by binding to a common site within Smoothened (SMO), a critical pathway component. Acquired mutations in SMO that map to these overlapping binding pockets compromise the potency and clinical efficacy of vismodegib and other clinically relevant agents in this space through an apparent class effect. As a consequence there are currently no visible therapeutic options for maintaining profound on-target efficacies in patients that present with recurrent disease harboring these point mutations.
We report here that itraconazole and arsenic trioxide, two FDA-approved agents recently reported to inhibit Hedgehog signaling through mechanisms distinct from that of current SMO antagonists, maintain potent inhibition of hedgehog signaling in the face of acquired SMO mutations, both as single agents and when used in combination. Using a preclinical mouse model of medulloblastoma that mimics clinical mechanisms of vismodegib-associated acquired resistance, we demonstrate that itraconazole and arsenic trioxide inhibit pathway activation, proliferation, and tumor growth of medulloblastoma harboring SMO-D477G mutation, both in vitro and in vivo. These drugs act as effectively in syngeneic models of medulloblastoma demonstrating constitutive signaling through wild-type SMO. Combination of itraconazole and arsenic trioxide further suppress tumor growth and improves survival in an orthotopic model of vismodegib-resistant medulloblastoma compared to either single agent alone. Furthermore, itraconazole and arsenic trioxide retain activity in all reported drug-resistant SMO mutants, including those reported in relation to NVP-LDE225 (Novartis).
Taken together, these results support clinical evaluation of itraconazole and arsenic trioxide for the treatment of Hh-dependent tumors, most notably those with acquired resistance to cyclopamine-mimics. These readily available FDA-approved agents have well defined pharmacokinetic and toxicity profiles. Our data support the rapid entry of itraconazole and arsenic trioxide into clinical testing to address patient populations for which vismodegib may not be available or is no longer efficacious.
Citation Format: Blake T. Aftab, James Kim, Jean Y. Tang, Emily M. King, Daniel Kim, Jynho Kim, Ervin H. Epstein, Philip A. Beachy, Charles M. Rudin. Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to vismodegib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5644. doi:10.1158/1538-7445.AM2013-5644